Immunosuppressive effects of pteridine derivatives

Abstract

This invention relates to a group of trisubstituted and tetrasubstituted pteridine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, dihydro- and tetrahydroderivatives and enantiomers, possessing unexpectedly desirable pharmaceutical properties, in particular which are highly active immunosuppressive agents, and as such are useful in the treatment in transplant rejection and/or in the treatment of certain inflammatory diseases. These compounds are also useful in preventing or treating cardiovascular disorders, allergic conditions, disorders of the central nervous system and cell proliferative disorders.

1 . A compound of the formula (Ia), (Ib) or (Ic),  
     
       
         
         
             
             
         
       
       R 1  is hydrogen, C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, wherein R 1  is unsubstituted or substituted with at least one substituent chosen from R 6 ,  
       R 2  is C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, or heteroaryalkyl wherein R 2  is unsubstituted or substituted with at least one substituent chosen from R 6 ,  
       R 2  is C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, or heteroaryalkyl wherein R 2  is unsubstituted or substituted with at least one substituent chosen from R 6 ,  
       or R 1  and R 2 , together with the nitrogen atom bearing them, form a 3-8-membered ring which may optionally comprises 0, 1 or 2 further heteroatoms chosen from N, O, and S, and wherein said 3-8-membered ring is unsubstituted or substituted by at least one substituent chosen from R 6 ,  
       R 3  is hydrogen, —CO-alkyl, —CO-alkylaryl, —CO-alkylheteroaryl, —CO-aryl, or —CO-heteroaryl,  
       R 4  is C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, —CO—O-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —CO-alkyl, —CO-aryl or —CO-heteroaryl wherein R 4  is unsubstituted or substituted with at least one substituent chosen from R 7 ,  
       R 4  is C 2 -C 20 -alkenyl, C 2 -C 20 -alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, heteroaryl, alkylheteroaryl, heteroarylalkyl, —CO—O-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —C—O-aryl or —CO-heteroaryl wherein R 4′  is unsubstituted or substituted with at least one substituent chosen from R 7 ,  
       R 5  is hydrogen, —CO-alkyl, —CO-alkylaryl, —CO-alkylheteroaryl, —CO-aryl, or CO-heteroaryl,  
       R 6  is —F, —OH, —O-(C 1 -C 10 )alkyl, —O-phenyl, —O—CO—(C 1 -C 10 )alkyl, —O—CO-aryl, —O—CO-heteroaryl, —NR 8 R 9 , oxo, phenyl, —CO—(C 1 -C 5 )-alkyl, —CF 3 , —CN, —CONR 8 R 9 , —COOH, —CO—O—C 1 -C 5 )-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —S(O) n —(C 1 -C 5 )-alkyl, —SO 2 NR 8 R 9 ,  
       R 7  is —F, —OH, —O—(C 1 -C 10 )-alkyl, —O-phenyl, —O—CO—(C 1 -C 10 )-alkyl, O—CO—O-aryl, O—CO—O-heteroaryl, —NR 8 R 9 , oxo, phenyl, —CO—(C 1 -C 5 )-alkyl, —CF 3 , —CN, —CONR 8 R 9 , —COOH, —CO—O—(C 1 -C 5 )alkyl, —CO—O-aryl, —S(O) n —(C 1 -C 5 )alkyl, —SO 2 —NR 8 R 9 ,  
       R 8  is hydrogen or C 1 -C 20 -alkyl, and  
       R 9  is hydrogen, C 1 -C 20 -alkyl, aryl, or heteroaryl,  
       wherein aryl groups are carbocyclic aryl groups, wherein heteroaryl groups are 5- to 7-membered unsaturated heterocycles comprising 1-4 heteroatoms chosen from O, N, and S,  
       or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.  
     
   
   
       2 . The compound of the formula (Ia) as claimed in  claim 1 , in which 
 R 1  is hydrogen, (C 1 -C 10 )-alkyl, (C 3 -C 8 )cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, (C 1 -C 3 )alkylaryl, (C 1 -C 3 )alkylheteroaryl, arylalkyl, or heteroarylalkyl, wherein R 1  is unsubstituted or the alkyl radicals are substituted with at least one substituent chosen from R 6 ,    R 2  is (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, (C 1 -C 3 )-alkylaryl, or (C 1 -C 3 ) alkylheteroaryl wherein R 2  is unsubstituted or the alkyl radicals are substituted with at least one substituent chosen from R 6 ,    or R 1  and R 2  may, together with the nitrogen atom bearing them, form a 3-8-membered ring, wherein said 3-8-membered ring optionally comprises 0, 1 or 2 further heteroatoms chosen from N, O, and S and wherein said 3-8-membered ring is unsubstituted or substituted by at least one substituent chosen from R 6 ,    R 3  is hydrogen, —CO—(C 1 -C 7 )-alkyl, —CO—(C 1 -C 3 ) alkylaryl, —CO—(C 1 -C 3 )-alkylheteroaryl, —CO—aryl, or —CO-heteroaryl,    R 4  is (C 1 -C 10 )alkyl, aryl, heteroaryl, (C 1 -C 3 )-alkylaryl, (C 1 -C 3 )-alkylheteroaryl —CO—O—(C 1 -C 5 )-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —CO—(C 1 -C 5 )alkyl, —CO-aryl or —CO-heteroaryl, wherein R 4  is unsubstituted or the alkyl radicals are substituted with at least one substituent chosen from R 7 ,    R 5  is hydrogen, CO—(C 1 -C 7 )-alkyl, —CO—(C 1 -C 3 )—alkylaryl, —C—(C 1 -C 3 )alkylheteroaryl, —CO-aryl, or —CO-heteroaryl,    R 6  is —F, —OH, —O—(C 1 -C 10 )-alkyl, —O-phenyl, —O—CO—(C 1 -C 10 )alkyl, —O—CO-aryl, —CO—heteroaryl, —NR 8 R 9 , oxo, phenyl, —CO—(C 1 -C 5 )—alkyl, —CF 3 , —CN, —CONR 8 R 9 , —CO OH, —CO—O—(C 1 -C 5 )-alkyl, —CO—O-aryl, —CO—O—heteroaryl, —S(O) n —(C 1 -C 5 )-alkyl, —SO 2 NR 8 R 9 ,    R 7  is —F, —OH, —O—(C 1 -C 10 )-alkyl, —O-phenyl, —O—CO—(C 1 -C 10 )-alkyl, —O—CO-aryl, —O—CO-heteroaryl, —NR 8 R 9 , oxo, phenyl, —CO—(C 1 -C 5 )-alkyl, —CF 3 , —CN, —CONR 8 R 9 , —COOH, —CO—O—(C 1 -C 5 )-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —S(O) n —(C 1 -C 5 )-alkyl, —SO 2 —NR 8 R 9 ,    R 8  is hydrogen or (C 1 -C 5 )alkyl, and    R 9  is hydrogen, (C 1 -C 5 )-alkyl or phenyl,    wherein each aryl group is phenyl or naphthyl, and    wherein said heteroaryl groups are 5- to 7-membered unsaturated heterocycles comprising 14 heteroatoms chosen from O, N, and S,    wherein said phenyl, naphthyl and heteroaryl groups are substituted groups which are substituted by at least one substituent chosen from halogen, (C 1 -C 5 )-alkyl or phenyl, —OH, —O—(C 1 -C 5 )-alkyl, (C 1 -C 2 )—alkylenedioxy, —N 8 R 9 , —NO 2 , —CO—(C 1 -C 5 )alkyl, —CF 3 , —CN, —CONR 8 R 9 , —COOH, —CO—O—(C 1 -C 5 )alkyl, —S(O)- n -(C 1 -C 5 )-alkyl, —SO 2 —NR 8 R 9 ,    wherein n is 0, 1 or 2,    or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.    
   
   
       3 . A compound of the formula (Ia) as claimed in  claim 1 , in which 
 R 1  is hydrogen, unsubstituted (C 2 -C 4 )alkyl, substituted (C 2-C4 )alkyl which is substituted by at least one R 6 , or (C 1 -C 2 )alkyl aryl or (C 1 -C 2 )-alkylheteroaryl,    R 2  is unsubstituted (C 2-C4 )-alkyl, substituted (C 2-C4 )-alkyl which is substituted by at least one R 6 , or cyclohexylmethyl or (C 1 -C 2 )-alkylaryl or (C 1 -C 2 ) alkylheteroaryl,    or R 1  and R 2 , together with the nitrogen atom bearing them, form a 5-7-membered ring wherein said 5-7-membered ring optionally comprises an additional heteroatom chosen from N, O, and S,    R 3  is hydrogen, —CO—(C 1 -C 3 )-alkyl, —CO-aryl or —CO-heteroaryl,    R 4  is aryl, heteroaryl, (C 1 -C 5 )alkyl, —CO—O-aryl or —CO-heteroaryl, wherein R 4  is unsubstituted or substituted with at least one substituent chosen from R 7 ,    R 5  is hydrogen,    R 6  is —OH, —O—(C 1 -C 3 )-alkyl, —NR 8 R 9  or —CO OH, and    R 7  is —OH, (C 1 -C 10 )-alkyloxy, phenoxy or oxo,    wherein each aryl group is phenyl,    wherein said heteroaryl groups are chosen from thiophenyl, furyl and pyridyl,    wherein said phenyl, thiophenyl, furyl or pyridyl groups are unsubstituted groups or substituted groups which are substituted by at least one substituent chosen from (C 1-C3 )-alkyl, halogen, (C 1 -C 3 )alkyloxy and (C 1 -C 2 )-alkylenedioxy, and    or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.    
   
   
       4 . A compound of the formula (Ia) as claimed in  claim 1 , in which 
 R 1  is arylmethyl,    R 2  is arylmethyl or cyclohexylmethyl,    or R 1  and R 2 , together with the nitrogen atom bearing them, form a pyrrolidine, piperidine, morpholine, dimethylmorpholine, thiomorpholine, or N—(C 1 -C 2 ) alky-lpiperazine ring,    R 3  is hydrogen,    R 4  is aryl or 1,2-dihydroxypropyl,    R 5  is hydrogen,    R 6  is —OH, —O—(C 1 -C 3 )-alkyl, —NR 8 R 9  or —COOH, and    R 7  is —OH, decyloxy or phenoxy,    wherein each aryl group is chosen from unsubstituted phenyl or substituted phenyl, which is substituted by at least one substituent chosen from (C 1 -C 3 )-alkyl, halogen and (C 1 -C 3 ) alkyloxy and (C 1 -C 2 )alkylenedioxy,    or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.    
   
   
       5 . The compound of formula (Ia) as claimed in  claim 1 , which is a tetrahydropteridine wherein R 4  is aryl, heteroaryl, (C 1 -C 5 )-alkyl —CO—O-aryl or —CO—O-(heteroaryl), and wherein said R 4  is unsubstituted or substituted with at least one substituent chosen from R 7 .  
   
   
       6 . The compound of formula (Ia) as claimed in  claim 1 , wherein 
 R 1  and R 2  are each, independently alkyl aryl, or heteroaryl, or    R 1  is hydrogen and R 2  is cycloalkyl or cycloalkylalkyl, and    wherein R 4  is aryl, (C 1 -C 5 )alkyl —CO—O-aryl or —CO—O-(heteroaryl), wherein said R 4  is unsubstituted or substituted with at least one substituent chosen from R 7 .    
   
   
       7 . A process for preparing a compound of formula (Ia), (Ib), or (Ic) as claimed in  claim 1  comprising reacting a compound of the formula II  
     
       
         
         
             
             
         
       
     
     with a compound of the formula III  
       HNR 1 R 2   (III)  
     which results in a compound of the formula IV  
     
       
         
         
             
             
         
       
     
     wherein the compound of formula IV is converted to a compound of formula V by catalytic hydrogenation  
     
       
         
         
             
             
         
       
     
     and wherein a compound of formula V is reacted with a compound of the formula VI  
     
       
         
         
             
             
         
       
     
     to give a compound of formula (Ia), (Ib), or (Ic).  
   
   
       8 . A pharmaceutical comprising a compound of formula (Ia), (Ib), or (Ic) as claimed in  claim 1  and an additional ingredient chosen from conventional excipients and additives.  
   
   
       9 . A method of treating or preventing strokes comprising administration of at least one pharmaceutical of  claim 8  to a patient in need thereof.  
   
   
       10 . A pteridine derivative having the formula:  
     
       
         
         
             
             
         
       
     
     wherein X represents a group with the formula NZ and wherein: 
 R 1  is aryl or arylalkyl;  
 Z is selected from the group consisting of hydrogen, aryl and arylalkyl;  
 R 2  is amino;  
 R 4  is hydrogen; and  
 R 3  is selected from the group consisting of aryl optionally substituted with one or more substituents selected from the group consisting of halogen and C 1-7  alkoxy; aromatic substituents substituted with an aliphatic spacer between the pteridine ring and the aromatic substituent, whereby said aliphatic spacer is a saturated or unsaturated aliphatic chain of 1 to 4 carbon atoms which may be halogenated or hydroxylated; and aliphatic chains of 2 to 7 carbon atoms optionally containing one or more functions selected from the group consisting of hydroxyl, ether and substituted or unsubstituted amino.  
 and/or a pharmaceutically acceptable addition salt thereof and/or a stereoisomer thereof.  
 
   
   
       11 . A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to  claim 10.